Poor cardiovascular health status among Chinese women.

BACKGROUND: Systematic investigation and analysis of cardiovascular health status (CVHS) of Chinese women is rare. This study aimed to assess CVHS and atherosclerotic cardiovascular disease (ASCVD) burden in the Chinese women physicians (CWP) and community-based non-physician cohort (NPC). METHODS: In this prospective, multicenter, observational study, CVHS using the American Heart Association (AHA) defined 7 metrics (such as smoking and fasting glucose) and ASCVD risk factors including hypertension, hyperlipidemia and type-2 diabetes were evaluated in CWP compared with NPC. RESULTS: Of 5832 CWP with a mean age of 44 ± 7 years, only 1.2% achieved the ideal CVHS and 90.1% showed at least 1 of the 7 AHA CVHS metrics at a poor level. Total CVHS score was significantly decreased and ASCVD risk burden was increased in postmenopausal subjects in CWP although ideal CVHS was not significantly influenced by menopause. Compared to 2596 NPC, fewer CWP had ≥ 2 risk factors (8% vs. 27%, P < 0.001); CWP scored significantly higher on healthy factors, a composite of total cholesterol, blood pressure, fasting glucose (P < 0.001), but, poorly on healthy behaviors (P < 0.001), specifically in the physical activity component; CWP also showed significantly higher levels of awareness and rates of treatment for hypertension and hyperlipidemia, but, not for type-2 diabetes. CONCLUSION: Chinese women's cardiovascular health is far from ideal and risk intervention is sub-optimal. Women physicians had lower ASCVD burden, scored higher in healthy factors, but, took part in less physical activity than the non-physician cohort. These results call for population-specific early and improved risk intervention.

Bloch oscillations in photonic spectral lattices through phase-mismatched four-wave mixing.

Here we investigate the Bloch oscillations (BOs) in a photonic spectral lattice created with four-wave mixing Bragg scattering (FWM-BS). By injecting a signal and two pumps with different frequencies into a silicon nitride waveguide, a spectral lattice can be created for the generated idlers through successive FWM-BS. The phase-mismatch during FWM-BS acts as an effective force that induces BOs in the spectral lattice. Both the oscillation period and amplitude are determined by the magnitude of the effective force. With cascaded FWM-BS processes, the spectrum of idlers experiences a directional shift as the phase differences of pumps are modulated. Additionally, introducing long-range couplings in the spectral lattice will change the trajectory of BOs within each period. The pattern of BOs for a single frequency input can also be tailored. This Letter provides a new platform to realize BOs in the frequency dimension and paves a promising way for broadband frequency control with all-optical schemes.

Prognostic value of plasma DPP4 activity in ST-elevation myocardial infarction.

BACKGROUND: Dipeptidyl peptidase-4 (DPP4) regulates blood glucose levels and inflammation, and it is also implicated in the pathophysiological process of myocardial infarction (MI). Plasma DPP4 activity (DPP4a) may provide prognostic information regarding outcomes for ST-segment elevation MI (STEMI) patients. METHODS: Blood samples were obtained from 625 consecutively admitted, percutaneous coronary intervention-treated STEMI patients with a mean age of 57 years old. DPP4a was quantified using enzymatic assays. RESULTS: The median follow-up period was 30 months. Multivariate Cox-regression analyses (adjusted for confounding variables) showed that a 1 U/L increase of DPP4a did not associate with risks of major adverse cardiac or cerebrovascular events (MACCE), cardiovascular mortality, MI, heart failure readmission, stroke, non-cardiovascular mortality and repeated revascularization. However, in a subset of 149 diabetic STEMI patients, DPP4a associated with an increased risk of MACCE (HR 1.16; 95% CI 1.04-1.30; p = 0.01). CONCLUSIONS: DPP4a did not associate with cardiovascular events and non-cardiovascular mortality in non-diabetic STEMI patients. However, DPP4a may be associated with future MACCE in diabetic STEMI patients. Trial registration NCT03046576, registered on 5 February, 2017, retrospectively registered.

Melatonin suppresses platelet activation and function against cardiac ischemia/reperfusion injury via PPARγ/FUNDC1/mitophagy pathways.

Platelet activation is a major (patho-) physiological mechanism that underlies ischemia/reperfusion (I/R) injury. In this study, we explored the molecular signals for platelet hyperactivity and investigated the beneficial effects of melatonin on platelet reactivity in response to I/R injury. After reperfusion, peroxisome proliferator-activated receptor γ (PPARγ) was progressively downregulated in patients with acute myocardial infarction undergoing coronary artery bypass grafting (CABG) surgery and in mice with I/R injury model. Loss of PPARγ was closely associated with FUN14 domain containing 1 (FUNDC1) dephosphorylation and mitophagy activation, leading to increased mitochondrial electron transport chain complex (ETC.) activity, enhanced mitochondrial respiratory function, and elevated ATP production. The improved mitochondrial function strongly contributed to platelet aggregation, spreading, expression of P-selectin, and final formation of micro-thromboses, eventually resulting in myocardial dysfunction and microvascular structural destruction. However, melatonin powerfully suppressed platelet activation via restoration of the PPARγ content in platelets, which subsequently blocked FUNDC1-required mitophagy, mitochondrial energy production, platelet hyperactivity, and cardiac I/R injury. In contrast, genetic ablation of PPARγ in platelet abolished the beneficial effects of melatonin on mitophagy, mitochondrial ATP supply, and platelet activation. Our results lay the foundation for the molecular mechanism of platelet activation in response to I/R injury and highlight that the manipulation of the PPARγ/FUNDC1/mitophagy pathway by melatonin could be a novel strategy for cardioprotection in the setting of cardiac I/R injury.

Assessment of a Drug-Eluting Balloon for the Treatment of de novo Coronary Lesions Guided by Optical Coherence Tomography: Study Protocol for a Randomized Controlled Trial.

BACKGROUND: The drug-eluting balloon (DEB) is a promising tool to prevent restenosis after coronary angioplasty. However, data on the outcomes of DEB in de novo lesions are scarce. Vessel recoil and constrictive remodeling are the dominant causes of restenosis after angioplasty. The use of cutting balloons (CB) may effectively reduce elastic recoil after balloon dilation. In this study, we evaluate the efficacy and safety of DEB in treating de novo coronary artery lesions, using a predilation strategy with cutting balloon (CB) dilation before DEB angioplasty. METHODS/DESIGN: We present the design of a prospective, single-center, open-label, randomized, 2-arm clinical trial aiming to assess whether or not the strategy of CB dilation before DEB angioplasty reduces the primary end point of late lumen loss (LLL) compared with drug-eluting stent (DES) implantation alone for de novo coronary artery lesions. A total of 120 patients will be randomly enrolled into the DEB or DES group (1:1 ratio). The primary end point is insegment LLL at 12 months as measured by optical coherence tomography (OCT). Secondary end points include procedural success, such as angiographic success and device success, and clinical outcomes including all-cause death, myocardial infarction, target vessel revascularization, target lesion revascularization, and stent thrombosis. DISCUSSION: The study will evaluate the clinical efficacy, angiographic outcomes, and safety of DEB after CB dilation compared with DES for the treatment of de novo coronary artery lesions guided by OCT.

Real-time observation of frequency Bloch oscillations with fibre loop modulation.

Bloch oscillations (BOs) were initially predicted for electrons in a solid lattice to which a static electric field is applied. The observation of BOs in solids remains challenging due to the collision scattering and barrier tunnelling of electrons. Nevertheless, analogies of electron BOs for photons, acoustic phonons and cold atoms have been experimentally demonstrated in various lattice systems. Recently, BOs in the frequency dimension have been proposed and studied by using an optical micro-resonator, which provides a unique approach to controlling the light frequency. However, the finite resonator lifetime and intrinsic loss hinder the effect from being observed practically. Here, we experimentally demonstrate BOs in a synthetic frequency lattice by employing a fibre-loop circuit with detuned phase modulation. We show that a detuning between the modulation period and the fibre-loop roundtrip time acts as an effective vector potential and hence a constant effective force that can yield BOs in the modulation-induced frequency lattices. With a dispersive Fourier transformation, the pulse spectrum can be mapped into the time dimension, and its transient evolution can be precisely measured. This study offers a promising approach to realising BOs in synthetic dimensions and may find applications in frequency manipulations in optical fibre communication systems.

The impact of 2019 novel coronavirus on heart injury: A Systematic review and Meta-analysis.

BACKGROUND: Evidence about COVID-19 on cardiac injury is inconsistent. OBJECTIVES: We aimed to summarize available data on severity differences in acute cardiac injury and acute cardiac injury with mortality during the COVID-19 outbreak. METHODS: We performed a systematic literature search across Pubmed, Embase and pre-print from December 1, 2019 to March 27, 2020, to identify all observational studies that reported cardiac specific biomarkers (troponin, creatine kinase-MB fraction, myoglobin, or NT-proBNP) during COVID-19 infection. We extracted data on patient demographics, infection severity, comorbidity history, and biomarkers during COVID-19 infection. Where possible, data were pooled for meta-analysis with standard (SMD) or weighted (WMD) mean difference and corresponding 95% confidence intervals (CI). RESULTS: We included 4189 confirmed COVID-19 infected patients from 28 studies. More severe COVID-19 infection is associated with higher mean troponin (SMD 0.53, 95% CI 0.30 to 0.75, p < 0.001), with a similar trend for creatine kinase-MB, myoglobin, and NT-proBNP. Acute cardiac injury was more frequent in those with severe, compared to milder, disease (risk ratio 5.99, 3.04 to 11.80; p < 0.001). Meta regression suggested that cardiac injury biomarker differences of severity are related to history of hypertension (p = 0.030). Also COVID19-related cardiac injury is associated with higher mortality (summary risk ratio 3.85, 2.13 to 6.96; p < 0.001). hsTnI and NT-proBNP levels increased during the course of hospitalization only in non-survivors. CONCLUSION: The severity of COVID-19 is associated with acute cardiac injury, and acute cardiac injury is associated with death. Cardiac injury biomarkers mainly increase in non-survivors. This highlights the need to effectively monitor heart health to prevent myocarditis in patients infected with COVID-19.

High-resolution MRI assessed carotid atherosclerotic plaque characteristics comparing men and women with elevated ApoB levels.

Previous studies demonstrated that men were more likely to have plaque rupture and are at greater risk for myocardial infarction and stroke than women. We evaluated differences in carotid plaque characteristics by MRI between men and women with mild-moderate atherosclerosis and elevated ApoB levels. One hundred eighty-two subjects (104 men and 78 women) with CAD or carotid stenosis (≥ 15% by ultrasound), ApoB ≥ 120 mg/dL and carotid MRI scan were included. Percent wall volume (%WV) was calculated as (wall volume/total vessel volume) × 100%. Three major plaque compositions, fibrous tissue (FT), calcification (CA) and lipid rich necrotic core (LRNC), were identified and quantified using published MRI criteria. Adventitial and plaque neovascularization as fractional plasma volume (Vp) and permeability as transfer constant (Ktrans) were analyzed using kinetic modeling. These characteristics were compared between men and women. Men, compared to women, were younger (54 ± 8 vs. 58 ± 8 years, p = 0.01), had higher rate of previous MI (46 vs. 26%, p = 0.005) but lower proportions of metabolic syndrome (37 vs. 59%, p = 0.003). After adjusting for between-gender differences, men were significantly more likely to have LRNC (OR 2.22, 95% CI 1.04-4.89, p = 0.04) and showed significantly larger %LRNC than women (diff = 4.3%, 95% CI 1.6-6.9%, p = 0.002), while %WV, FT, and CA were similar between men and women. There were no statistically significant differences in adventitial and plaque Vp or Ktrans. Men were significantly more likely to have LRNC and had larger LRNC than women. However, men and women showed relatively similar levels of adventitial and plaque neovascularization and permeability.Trial registration: NCT00715273 at ClinicalTrials.gov. Registered 15 July 2008, retrospectively registered.

Risk factors for repeat percutaneous coronary intervention in young patients (≤45 years of age) with acute coronary syndrome.

BACKGROUND: The incidences of premature coronary heart disease present a rising trend worldwide. The possible risk factors that may predict the incidence of repeat percutaneous coronary intervention (PCI) in premature acute coronary syndrome (ACS) remains unclear. METHODS: A total of 203 patients ≤45 years with ACS from Chinese PLA General Hospital who have undergone angiography twice were included in this report. Data were collected from medical records of patients during hospitalization. Baseline characteristics which have significant differences in the univariate analysis were enrolled into the multiple logistic regression analysis. According to the odds ratio (OR) of these variables, different values were assigned to build a risk model to predict the possible risk of the premature ACS patients undergoing repeat PCI. RESULTS: Of the 203 young patients, 88 patients (43.3%) underwent repeat PCI. The intermit time (OR 1.002, (95% CI [1.001-1.002])), diastolic blood pressure of second procedure (OR 0.967, (95% CI [0.938-0.996])), stent diameter (OR 0.352, (95% CI [0.148-0.840])), HbA1C of the first procedure (OR 1.835, (95% CI [1.358-2.479])), and Troponin T of the second procedure (OR 1.24, (95% CI [0.981-1.489])) were significantly associated with the incidence of repeat PCI in patients with premature ACS. An aggregate score between 0 and 6 was calculated based on these cutpoints. CONCLUSION: For young patients with premature ACS, risk of undergoing repeat PCI was high. HbA1C was a significant, independent predictor for the incidence of repeat revascularization, and weighed more than traditional lipid profile. The glucose metabolism and disorders in patients with premature ACS should be routinely screened.

Subclinical hypothyroidism is associated with lipid-rich plaques in patients with coronary artery disease as assessed by optical coherence tomography.

BACKGROUND: Subclinical hypothyroidism (SCH) has recently been acknowledged as an unconventional risk factor for coronary artery disease (CAD) and characterized by poor prognosis, which may be due to atherosclerotic plaque characteristics. We conducted this study to observe coronary plaque characteristics in coronary artery disease patients with concomitant SCH. METHODS: Patients with coronary artery disease were enrolled in the study and divided into an SCH group (patients, n = 26; plaques, n = 35) and a non-SCH group (patients, n = 52; plaques, n = 66). They were divided 1: 2 according to propensity-matched analysis including age, diabetes mellitus, gender, CAD severity and culprit vessel. Optical coherence tomography (OCT) imaging was performed on all patients, and images were analyzed by two independent investigators. Lipid-rich plaques (LRP), the precursor of vulnerable plaques, were defined as having more than one quadrant occupied with lipid pool. Maximum lipid arcs were simultaneously recorded. Fibrotic plaques and calcific plaques were also identified. The presence of coronary dissection, plaque erosion, thrombus, macrophage, calcific nodule, thin-cap fibroatheroma and micro channel were all noted. RESULTS: The ratio of LRP in SCH group was significantly higher than that in non-SCH group (54% vs. 30.3%, P = 0.037). That was the case as well for the maximum lipid arcs value (181.5° ± 61.6° vs. 142.1° ± 35.9°, P = 0.046). While thin-cap fibroatheroma (TCFA) was detected, no difference was identified between the two groups in either TCFA ratio (20% vs. 16.7%, P = 0.579) or fibrous cap thickness (57.5 ± 14.0 vs. 63.5 ± 10.7 µm, P = 0.319). Other OCT characteristics such as dissection, plaque erosion, thrombus, macrophage shadow and calcific nodule were also similar. CONCLUSION: Higher ratio of LRP with greater lipid arc in SCH patients may be related to the plaque instability and poor prognosis in CAD patients with SCH.

Clinical characteristics and prognosis of acute myocardial infarction in young smokers and non-smokers (≤ 45 years): a systematic review and meta-analysis.

The effect of smoking on the prognosis of young patients with acute myocardial infarction (AMI) is inconclusive. We enrolled 2188 young AMI patients (≤ 45 years) from the cardiac center of the Chinese PLA General Hospital and Anzhen Hospital and analyzed their clinical characteristics and prognosis. We also searched the PubMed, EMBASE, and Cochrane Central Register of Controlled Trials electronic databases for January 2001 to March 2017 and considered for inclusion in a meta-analysis those clinical trials that compared prognoses of young smokers and non-smokers with AMI. The proportion of males and alcohol users was higher in young AMI smokers than in non-smokers; the proportion of hypertension was slightly lower. There was no difference in medical treatment between smokers and non-smokers. No differences were evident between smokers and non-smokers regarding in-hospital cardiac events and major adverse cardiovascular events on follow-up, including incidence of stroke. For young AMI patients, smoking did not lead to poorer prognosisin comparison with not smoking. This "smoker's paradox" needs to be confirmed by more randomized controlled multicenter prospective clinical trials.

Exendin-4 promotes proliferation of adipose-derived stem cells through ERK and JNK signaling pathways.

Adipose-derived stem cell (ADSC) transplantation has emerged as a potential tool for the treatment of cardiovascular disease. However, with a limited renewal capacity and the need for mass cells during the engraftment, strategies are needed to enhance ADSC proliferative capacity. In this study, we explored the effects of exendin-4 (Ex-4), a glucagon-like peptide-1 analog, on the growth of ADSCs, focusing in particular on c-Jun NH2-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) signaling pathways. Firstly, ADSCs were isolated and cultured in vitro. Then, flow cytometry demonstrated that ADSCs were positive for CD90 and CD29 but negative for CD31, CD34, and CD45. Ex-4 (0-50 nM) treatment increased ADSC proliferation in a dose-dependent manner but had no effects on stem cell markers of ADSCs. Moreover, we found that Ex-4 treatment elevated the phosphorylation levels of the JNK and ERK signaling pathways. Furthermore, utilization of Ex-4 also promoted cyclin D1 and cyclin E protein expression, which was accompanied by more Edu(+) cells and a higher percentage of cells in the S-phase of the cell cycle after Ex-4 treatment. In parallel, the application of inhibitors SP600125 and PD98059, inhibitors of the JNK and ERK signaling pathways, respectively, not only reversed such effects of Ex-4 on JNK and ERK but also resulted in lower percentages of S-phase cells and fewer numbers of Edu(+) cells. In summary, Ex-4 has no effects on stem cell markers in ADSCs but promotes ADSC growth via JNK and ERK signaling pathways.

Homocysteine is associated with the progression of non-culprit coronary lesions in elderly acute coronary syndrome patients after percutaneous coronary intervention.

BACKGROUND: The influence of homocysteine (Hcy) on the migration and proliferation of vascular smooth muscle cells has been well established. However, the impact of Hcy levels on the progression of non-culprit coronary lesions (NCCLs) is controversial. This study aims to evaluate whether the plasma level of Hcy is related to the progression of NCCLs after percutaneous coronary stent implantation in elderly patients with acute coronary syndrome (ACS). METHODS: A total of 223 elderly patients (≥ 65 years old) with ACS undergoing stent implantation and follow-up coronary angiography were enrolled. Laboratory determination comprised of blood sample evaluation for Hcy was carried out before baseline coronary intervention. The patients were classified into two groups according to the blood Hcy tertiles (≥ 15 mmol/L or < 15 mmol/L). Patients were followed up for 12.2 months. NCCL progression was assessed by three-dimensional quantitative coronary angiography. RESULTS: A significantly higher ratio of NCCL progression was observed in the group with baseline Hcy concentrations above 15 mmol/L compared to the group with concentrations below 15 mmol/L (41/127, 32.3% vs. 14/96, 14.6%, P = 0.002). Multivariate Cox regression analysis showed that Hcy and diabetes mellitus were independent risk factors for NCCL progression. The crude hazard ratio (HR) of NCCL progression for Hcy level was 1.056 (95% CI: 1.01-1.104, P = 0.015). The adjusted HR of NCCL progression for Hcy level was 1.024 (95% CI: 1.007-1.042, P = 0.007). The adjusted HR of NCCL progression for diabetes mellitus was 1.992 (95% CI: 1.15-3.44, P = 0.013). CONCLUSIONS: Hcy is an independent risk factor for NCCL progression after 12 months of follow-up in elderly patients with ACS who has undergone percutaneous coronary stenting.

Liraglutide protects cardiac microvascular endothelial cells against hypoxia/reoxygenation injury through the suppression of the SR-Ca(2+)-XO-ROS axis via activation of the GLP-1R/PI3K/Akt/survivin pathways.

Microvascular endothelial cells (CMECs) oxidative damage resulting from hypoxia/reoxygenation (H/R) injury is responsible for microcirculation perfusion disturbances and the progression of cardiac dysfunction. However, few strategies are available to reverse such pathologies. Here, we studied the effects and mechanisms of liraglutide on CEMCs oxidative damage, focusing in particular on calcium overload-triggered free radical injury signals and the GLP-1R/PI3K/Akt/survivin survival pathways. The results indicate that H/R increased IP3R expression but reduced SERCA2a expression, which rapidly raised intracellular Ca(2+) levels, subsequently leading to Ca(2+)-dependent xanthine oxidase (XO) activation, reactive oxygen species (ROS) production and the cellular apoptosis of CMECs. However, liraglutide pretreatment abrogated Ca(2+)-mediated oxidative apoptosis. Furthermore, liraglutide regulated the rate of IP3R/SERCA2a gene transcription and conserved SERCA2a-ATPase activity via the maintenance of ATP production under H/R, which drove excessive Ca(2+) reflux to the sarcoplasmic reticulum (SR) and inhibited Ca(2+) release from the SR, ultimately restoring Ca(2+) homeostasis. Furthermore, the regulatory role of liraglutide on Ca(2+) balance in conjunction with its up-regulation of superoxide dismutase, glutathione and glutathione peroxidase collectively scavenged the excess ROS under H/R. Moreover, we showed that liraglutide strengthened Akt phosphorylation and subsequently survivin expression. In addition, both the blockade of the GLP-1R/PI3K/Akt pathways and the siRNA-mediated knockdown of survivin abolished the protective effects of liraglutide on SR-Ca(2+) function and CMECs oxidative apoptosis. In summary, this study confirmed that H/R induced CMECs oxidative damage through the SR-Ca(2+)-XO-ROS injury signals and that liraglutide pretreatment may suppress such CMECs damage through the PI3K/Akt/survivin pathways.

Influence of increased epicardial adipose tissue volume on 1-year in-stent restenosis in patients who received coronary stent implantation.

BACKGROUND: Epicardial adipose tissue (EAT) is significantly associated with the formation and composition of coronary atherosclerotic plaque, cardiac events and the clinical prognosis of coronary heart disease. But, whether increased EAT deposition may affect the incidence of in-stent restenosis (ISR) is currently unclear. This study used coronary computed tomography angiography (CCTA) as a mean to investigate whether increased EAT volume was associated with ISR. METHODS: A total of 364 patients who underwent 64-slice CCTA examination for the evaluation of suspected coronary artery disease, and subsequently underwent percutaneous coronary intervention (PCI) for the first time, and then accepted coronary angiography (CA) follow-up for ISR examination in one year, were retrospectively included in this study. EAT volume was measured by CCTA examination. CA follow-up was obtained between 9 and 15 months. ISR was defined as ≥ 50% luminal diameter narrowing of the stent segment or peri-stent segment. EAT volume was compared between patients with and without ISR and additional well-known predictors of ISR were compared. RESULTS: EAT volume was significantly increased in patients with ISR compared with those without ISR (154.5 ± 74.6 mL vs. 131.0 ± 52.2 mL, P < 0.001). The relation between ISR and EAT volume remained significant after adjustment for conventional cardiovascular risk factors and angiographic parameters. CONCLUSIONS: EAT volume was related with ISR and may provide additional information for future ISR.

Exendin-4 protects adipose-derived mesenchymal stem cells from apoptosis induced by hydrogen peroxide through the PI3K/Akt-Sfrp2 pathways.

Adipose-derived mesenchymal stem cells (ADMSCs)-based therapy is a promising modality for the treatment of myocardial infarction in the future. However, the majority of transplanted cells are readily lost after transplantation because of hypoxia and oxidative stress. An efficient means to enhance the ability of ADMSCs to survive under pathologic conditions is required. In our study, we explored the effects of exendin-4 (Ex-4) on ADMSCs apoptosis in vitro induced by hydrogen peroxide, focusing in particular on mitochondrial apoptotic pathways and PI3K/Akt-secreted frizzled-related protein 2 (Sfrp2) survival signaling. We demonstrated that ADMSCs subjected to H2O2 for 12h exhibited impaired mitochondrial function and higher apoptotic rate. However, Ex-4 (1-20 nM) preconditioning for 12h could protect ADMSCs against H2O2-mediated apoptosis in a dose-dependent manner. Furthermore, Ex-4 pretreatment upregulated the levels of superoxide dismutase and glutathione as well as downregulating the production of reactive oxygen species and malondialdehyde. Western blots revealed that increased antiapoptotic proteins Bcl-2 and c-IAP1/2 as well as decreased proapoptotic proteins Bax and cytochrome c appeared in ADMSCs with Ex-4 incubation, which inhibited the caspase-9-involved mitochondrial apoptosis pathways with evidence showing inactivation of caspase-9/3 and preservation of mitochondrial membrane potential. Furthermore, we illustrated that Ex-4 enhanced Akt phosphorylation, which increased the expression of Sfrp2. Notably, blockade of the PI3K/Akt pathway or knockdown of Sfrp2 with siRNA obviously abolished the protective effects of Ex-4 on mitochondrial function and ADMSCs apoptosis under H2O2. In summary, this study confirmed that H2O2 induced ADMSCs apoptosis through mitochondria-dependent cell death pathways, and Ex-4 preconditioning may reduce such apoptosis of ADMSCs through the PI3K/Akt-Sfrp2 pathways.

In vivo and in vitro suppression of hepatocellular carcinoma by EF24, a curcumin analog.

The synthetic compound 3,5-bis(2-flurobenzylidene)piperidin-4-one (EF24) is a potent analog of curcumin that exhibits enhanced biological activity and bioavailability without increasing toxicity. EF24 exerts antitumor activity by arresting the cell cycle and inducing apoptosis, suppressing many types of cancer cells in vitro. The antiproliferative and antiangiogenic properties of EF24 provide theoretical support for its development and application to liver cancers. We investigated the in vitro and in vivo activities of EF24 on liver cancer to better understand its therapeutic effects and mechanisms. EF24 induced significant apoptosis and G2/M-phase cell cycle arrest in mouse liver cancer cell lines, Hepa1-6 and H22. The expression levels of G2/M cell cycle regulating factors, cyclin B1 and Cdc2, were significantly decreased, pp53, p53, and p21 were significantly increased in EF24-treated cells. In addition, EF24 treatment significantly reduced Bcl-2 concomitant with an increase in Bax, enhanced the release of cytochrome c from the mitochondria into the cytosol, resulting in an upregulation of cleaved-caspase-3, which promoted poly (ADP-ribose) polymerase cleavage. EF24-treated cells also displayed decreases in phosphorylated Akt, phosphorylated extracellular signal-regulated kinase and vascular endothelial growth factor. Our in vitro protein expression data were confirmed in vivo using a subcutaneous hepatocellular carcinoma (HCC) tumor model. This mouse HCC model confirmed that total body weight was unchanged following EF24 treatment, although tumor weight was significantly decreased. Using an orthotopic HCC model, EF24 significantly reduced the liver/body weight ratio and relative tumor areas compared to the control group. In situ detection of apoptotic cells and quantification of Ki-67, a biomarker of cell proliferation, all indicated significant tumor suppression with EF24 treatment. These results suggest that EF24 exhibits anti-tumor activity on liver cancer cells via mitochondria-dependent apoptosis and inducing cell cycle arrest coupled with antiangiogenesis. The demonstrated activities of EF24 support its further evaluation as a treatment for human liver cancers.